UCSF

The cell relies on absolute symmetry to accurately segregate its genome into two daughter cells. The start of this symmetry is during DNA replication, where one chromosome is completely and precisely duplicated to produce two exact copies. These two copies are cohesed together and brought under tension by the mitotic spindle, which attaches microtubules to the kinetochore complexes assembled on centromeres. Lack of tension is sensed by the spindle assembly checkpoint (SAC), but when each chromatid pair is properly bioriented, the chromosomes are freed of their ties and are pulled to opposite spindle poles. Thus, bilateral symmetry is essential for proper chromosome segregation.

Despite the checkpoints and intrinsic nature of the system to biorient sister chromatids, chromosome missegregation does occur. The result is cellular progeny that is aneuploid, or having an abnormal number of chromosomes. Aneuploidy is a hallmark of cancer, so understanding how chromosome segregation could go awry has been intensely studied. Disrupting the spindle microtubules, the kinetochores, cohesin, or the SAC have proven to increase missegregation rates in model systems, however, this machinery is rarely inoperative in actual tumor samples, leaving scientists to search for other sources of aneuploidy.

Due to the essential role of bilateral symmetry in chromosome segregation, I investigated whether it could be disrupted outside of mitosis. The symmetry of the sister chromatids relies on a "once and only once" round of replication; if a re-replication event was to occur that encompassed a centromere, then the bilateral nature of the sister chromatid pair would be abolished. Using the Li Lab re-replication genetic system, I showed that centromeric re-replication can induce aneuploidy, either through.the missegregation of the re-replicated chromosome or by the creation of an entire, whole chromosome. Microscopic analysis of newly re-replicated cells demonstrates the extra centromere is able to attach to the mitotic spindle, indicating it may produce a merotelic attachment that could lead to the chromatid's missegregation or enhance the fragility of the re-replication bubble. Together, I have shown that centromeric re-replication is a potent inducer of aneuploidy, which may spur investigation into the role re-replication may play in aneupoidy in cancer.